DESCRIPTION (Verbatim From the Applicant's Abstract): This project aims to elucidate the role of cyclic nucleotide-activated ion channels in neuronal connectivity and differentiation. We will use a mammalian model system amenable to genetic manipulation to study the fate of neuronal progenitors and mature olfactory sensory neurons with specific defects in second messenger signaling pathways. We will investigate the role of activity dependent processes in the proliferation of neuronal precursors, the initial projection of sensory neurons to their target and the stabilization of neuronal connections. Molecular biological, genetic, biochemical and electrophysiological methods will be utilized to understand the role of the OcNC-1 and OcNC-2 ion channel subunits in olfactory neuronal differentiation and establishment of projections to the olfactory bulb. The absence of synaptic input to olfactory neurons results in the OcNC-1 and OcNC-2 subunits providing a central mechanism for initiating activity-dependent processes in development and subsequent odor transduction. The OcNC-1 protein functions, at least in part, to convert cyclic nucleotide increases into calcium influx and initiate membrane depolarization. In parallel, we will test the hypothesis that a second olfactory neuronal cyclic nucleotide channel, OcNC-2, has a distinct role in mediating critical stages of neuronal differentiation. Specifically, the application will (1) Characterize the contributions of the OcNC-1 and OcNC-2 channel subunits to the normal development of the olfactory epithelium. We will test the hypothesis that olfactory cyclic nucleotide-activated channels contribute to the development of the olfactory system and the maturation of appropriate connections. (2) Examine the effects of competition between normal and OcNC-1 deficient neurons and the role of neuronal activity in cellular differentiation and the establishment and maintenance of connectivity. These studies will incorporate a unique system to generate mice possessing an olfactory epithelium comprised of a mosaic of wild type and OcNc-1-deficient sensory neurons. (3) Test the hypothesis that the OcNC-2 subunit contributes to the functional properties of the cyclic nucleotide-mediated transduction pathway in mature olfactory neurons. This application will utilize the special properties of the olfactory system to elucidate the contribution of activity dependent processes in the normal and abnormal development of neuronal cells.